Synthesis, biological evaluation and molecular docking of new triphenylamine-linked pyridine, thiazole and pyrazole analogues as anticancer agents.

A new series of pyridine, thiazole, and pyrazole analogues were synthesized. The pyridone analogues 4a-e were synthesized by treating N-aryl-2-cyano-3-(4-(diphenylamino)phenyl)acrylamides 3a-e with malononitrile. Many 4-arylidene-thiazolidin-5-one analogues 6a-d were obtained by Knoevenagel reactions of 4-(diphenylamino)benzaldehyde (1) with their corresponding thiazolidin-5-one derivatives 5a-d. The structural elucidation of the products was proven by the collections of spectroscopic methods such as IR, 1H NMR, 13C NMR, and MS data. Their anti-cancer activity was examined against two cell lines, MDA-MB-231 (mammary carcinomas) and A-549 (lung cancer). Compared with cisplatin as a reference standard drug, 6-amino-4-(4-(diphenylamino)phenyl)-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3,5-dicarbonitrile (4b) and 6-amino-4-(4-(diphenylamino)phenyl)-1-(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (4e) exhibited better efficiency against the A-549 cell line, with IC50 = 0.00803 and 0.0095 µM, respectively. Also, these compounds 4b and 4e showed the most potency among the examined compounds against MDA-MB-231 with IC50 = 0.0103 and 0.0147 µM, respectively. The newly synthesized compounds were docked inside the active sites of the selected proteins and were found to demonstrate proper binding. 2-Cyano-2-(4,4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)-N-(p-tolyl)acetamide (6c) offered the highest binding affinity (- 8.1868 kcal/mol) when docked into (PDB ID:2ITO), in addition to 2-cyano-N-(4-(diethylamino)phenyl)-2-(4-(4-(diphenylamino)benzylidene)-5-oxo-3-phenylthiazolidin-2-ylidene)acetamide (6a) gave the highest energy score (- 9.3507 kcal/mol) with (PDB ID:2A4L).

Novel 2-(5-Aryl-4,5-Dihydropyrazol-1-yl)thiazol-4-One as EGFR Inhibitors: Synthesis, Biological Assessment and Molecular Docking Insights.

Introduction: Epidermal growth factor receptor (EGFR) regulates several cell functions which include cell growth, survival, multiplication, differentiation, and apoptosis. Currently, EGFR kinase inhibitors are of increasing interest as promising targeted antitumor therapeutic agents. Methods: Different thiazolyl-pyrazoline derivatives (7a-o) were synthesized and were first tested for anti-proliferative effect towards the A549 lung cancer cell line and the T-47D breast cancer cell line in MTT assay. Thereafter, thiazolyl-pyrazolines (7b, 7g, 7l, and 7m) were subsequently evaluated for their PK inhibition for EGFR. Moreover, representative promising derivatives (7g and 7m) in cytotoxic and PK inhibition assays were tested to investigate their impact on the apoptosis and cell cycle phases in T-47D cells in order to explore more insights into the antitumor actions of the target thiazolyl-pyrazolines. Furthermore, docking studies were accomplished to evaluate the patterns of binding of thiazolyl-pyrazolines 7b, 7g, 7l, and 7m in the EGFR active pocket (PDB ID: 1M17). Results: Testing the thiazolyl pyrazoline compounds 7a-o on A549 and T-47D cell lines showed IC50 arrays between 3.92 and 89.03 µM, and between 0.75 and 77.10 µM, respectively. Also, the tested thiazolyl-pyrazolines (7b, 7g, 7l, and 7m) demonstrated significant sub-micromolar EGFR inhibitory actions with IC50 values 83, 262, 171 and 305 nM, respectively, in comparison to erlotinib (IC50 =57 nM). Discussion: Generally, it was observed that the tested thiazolyl pyrazolines showed more potent antiproliferative activity toward breast cancer cells T-47D than toward lung cancer cell lines A549. In particular, thiazolyl pyrazolines 7g and 7m showed the best activity against A549 cells (IC50 = 3.92 and 6.53 µM) and T-47D cells (IC50 = 0.88 and 0.75 µM). Compounds 7g and 7m provoked a sub-G1 phase arrest and cell apoptosis which are in agreement with the expected outcome of EGFR inhibition. Finally, the molecular docking of 7g and 7m in the active site of EGFR revealed a common binding pattern similar to that of erlotinib which involves the accommodation of the 1,3 thiazol-4-one ring and pyrazoline ring of target compounds in the binding region of erlotinib's quinazoline ring and anilino moiety.

A Robust and Highly Precise Alternative against the Proliferation of Intestinal Carcinoma and Human Hepatocellular Carcinoma Cells Based on Lanthanum Strontium Manganite Nanoparticles.

In this report, lanthanum strontium manganite at different Sr2+ ion concentrations, as well as Gd3+ or Sm3+ ion substituted La0.5-YMYSr0.5MnO3 (M = Gd and Sm, y = 0.2), have been purposefully tailored using a sol gel auto-combustion approach. XRD profiles confirmed the formation of a monoclinic perovskite phase. FE-SEM analysis displayed a spherical-like structure of the La0.8Sr0.2MnO3 and La0.3Gd0.2Sr0.2MnO3 samples. The particle size of the LSM samples was found to decrease with increased Sr2+ ion concentration. For the first time, different LSM concentrations were inspected for their cytotoxic activity against CACO-2 (intestinal carcinoma cells) and HepG-2 (human hepatocellular carcinoma cells). The cell viability for CACO-2 and HepG-2 was assayed and seen to decrease depending on the Sr2+ ion concentration. Half maximal inhibitory concentration IC50 of CACO-2 cell and HepG-2 cell inhibition was connected with Sr2+ ion ratio. Low IC50 was noticable at low Sr2+ ion content. Such results were correlated to the particle size and the morphology. Indeed, the IC50 of CACO-2 cell inhibition by LSM at a strontium content of 0.2 was 5.63 ± 0.42 µg/mL, and the value increased with increased Sr2+ ion concentration by up to 0.8 to be = 25 ± 2.7 µg/mL. Meanwhile, the IC50 of HepG-2 cell inhibition by LSM at a strontium content of 0.2 was 6.73 ± 0.4 µg/mL, and the value increased with increased Sr2+ ion concentration by up to 0.8 to be 31± 3.1 µg/mL. All LSM samples at different conditions were tested as antimicrobial agents towards fungi, Gram positive bacteria, and Gram negative bacteria. For instance, all LSM samples were found to be active towards Gram negative bacteria Escherichia coli, whereas some samples have presumed antimicrobial effect towards Gram negative bacteria Proteus vulgaris. Such results confirmed that LSM samples possessed cytotoxicity against CACO-2 and HepG-2 cells, and they could be considered to play a substantial role in pharmaceutical and therapeutic applications.